Influenza is caused by an RNA virus of the orthomyxoviridae family. There are three types of influenza viruses: A, B and C. Influenza A viruses infect mammals (e.g. humans, pigs, ferrets, horses) and birds. Influenza A viruses are a global health concern, and have been responsible for three major pandemics that have killed over 50 million people worldwide since 1900. For example, the devastating “Spanish flu” (H1N1 influenza A virus) in 1918 killed more than twenty million people worldwide. Subsequent pandemics, including the Asian flu pandemic in 1957 (H2N2), the Hong Kong flu pandemic in 1968 (H3N2), the re-emergence of H1N1 (Russian flu) in 1970, along with the avian flu virus H5N1 in 1997 and 2003, suggest that pandemic influenza or possible bioterrorist attacks with flu viruses remains a major threat to global health and safety. Despite the profound effects of influenza viruses on public health throughout history, the standard treatments for influenza infections still remain inadequate.
The most common targets for small molecule-based therapeutics to combat influenza virulence include the proton-selective M2 ion channel and the protein neuramidase (NA). The M2 ion channel is integral to the maintenance of the viral envelope of the influenza A virus, while NA promotes budding of nascent viral particles from the host cell. Resistance is common among inhibitors directed at both targets, and has become widespread in clinical isolates. Almost 100% of the 2008 influenza H1N1 virus (swine flu) samples were resistant to the neuramidase inhibitor oseltamivir (Tamiflu), while more than 90% of the H3N2 viruses were resistant to the M2 channel blocker adamantanes.
Besides resistance, factors including mode of administration and environmental impact affect the development of effective influenza treatments. For instance, Zanamivir (Relenza) can only be administered by inhalation and may not reach infected lung tissue that is poorly aerated. Further, the widely used and stockpiled drug Oseltamivir is not degraded during the course of normal sewage treatment and thus poses environmental concerns.
There exists a need for antiviral compounds that inhibit influenza replication, reduce virulence of the influenza infection, and/or prevent influenza infection.
Therefore, it is an object of the invention to provide antiviral compounds that effectively treat or prevent viral infections, particularly influenza infections, methods of making the compounds, and methods of using the compounds.